ORGANIC LETTERS
cis-endo-Bicyclo[1.1.1]pentane-1,2,3,4tetracarboxylic Acid and Its Derivatives
2006 Vol. 8, No. 4 749-752
Ctibor Mazal,*,‡ Ondrˇej Sˇ karka,‡ Jirˇ´ı Kaleta,‡ and Josef Michl† Department of Organic Chemistry, Masaryk UniVersity, Kotla´ rˇska´ 2, 611 37 Brno, Czech Republic, and Department of Chemistry and Biochemistry, UniVersity of Colorado, Boulder, Colorado 80309-0215
[email protected] Received December 14, 2005
ABSTRACT
We report the synthesis of cis-endo-bicyclo[1.1.1]pentane-1,2,3,4-tetracarboxylic acid and several of its derivatives with differentiated bridgehead and bridge positions, starting with tetracyclo[3.2.0.01,6.02,6]heptane.
We are interested in the possibility that close spatial proximity of multiple functional groups crowded on a small cage, such as bicyclo[1.1.1]pentane, might lead to unusual properties as a result of their mutual interactions. In addition to offering interesting substrates for reactivity studies, highly functionalized bicyclo[1.1.1]pentanes might also provide future access to bridge-functionalized [1.1.1]propellanes and thus to laterally substituted [n]staffane molecular rods.1 Although numerous bicyclo[1.1.1]pentanes substituted only in the bridgehead positions are known,2 those also functionalized on the bridges are extremely rare. 1,3Disubstituted 2,2-dichloro and 2,2-dibromo derivatives were prepared by reaction of bicyclo[1.1.0]butane derivatives with dichloro3-6 and dibromo carbenes, respectively. Such tetrasubstituted bicyclo[1.1.1]pentanes were also prepared by direct chlorination of bicyclo[1.1.1]pentane-1,3-dicarboxylic acid, its dichloride,7 and 1,3-dibromobicyclo[1.1.1]pentane.8 ‡
Masaryk University. University of Colorado. (1) Schwab, P. F. H.; Levin, M. D.; Michl, J. Chem. ReV. 1999, 99, 1863. (2) Levin, M. D.; Kaszynski, P.; Michl, J. Chem. ReV. 2000, 100, 169. (3) Applequist, D. E.; Wheeler, J. W. Tetrahedron Lett. 1977, 3411. (4) Applequist, D. E.; Renken, T. L.; Wheeler, J. W. J. Org. Chem. 1982, 47, 4985. (5) Hall, H. K., Jr.; Smith, C. D.; Blanchard, E. P., Jr.; Cherkofsky, S. C.; Sieja, J. B. J. Am. Chem. Soc. 1971, 93, 121. (6) Potekhin, K. A.; Maleev, A. V.; Struchkov, Yu. T.; Surmina, L. S.; Koz’min, A. S.; Zefirov, N. S. Dokl. Akad. Nauk SSSR Ser. Khim. 1988, 298, 123. (7) Robinson, R. E.; Michl, J. J. Org. Chem. 1989, 54, 2051. †
10.1021/ol053039n CCC: $33.50 Published on Web 01/20/2006
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Interestingly, 2-monochloro derivatives did not accumulate and had to be obtained by subsequent partial dehalogenation. Direct fluorination of the 1,3-dicarboxylic acid provided almost all of the possible fluorinated diacids which were separated and used for an investigation of long-range NMR coupling constants.9,10 Some 2,2-difluoro derivatives have been patented as structural units for liquid crystals.11 Carbonlinked bridge substitution is only represented by 2,4-ethano12 and 2,4-propano13-16 bridged derivatives (tricyclo[3.2.0.02,6]heptanes and tricyclo[4.2.0.02,7]octanes, respectively) and by poly[1.1.1]propellanes, whose bicyclo[1.1.1]pentane cages carried an alkyl chain,17 including one with a remote hydroxyl function18 used to anchor a dendritic fragment.19 (8) Hamrock, S. J.; Michl, J. J. Org. Chem. 1992, 57, 5027. (9) Levin, M. D.; Hamrock, S. J.; Kaszynski, P.; Shtarev, A. B.; Levina, G. A.; Noll, B. C.; Ashley, M. E.; Newmark, R.; Moore, G. G. I.; Michl, J. J. Am. Chem. Soc. 1997, 119, 12750. (10) Shtarev, A. B.; Pinkhassik, E.; Levin, M. D.; Stibor, I.; Michl, J. J. Am. Chem. Soc. 2001, 123, 3484. (11) Yano, H.; Takeuchi, H. Jpn. Kokai Tokkyo Koho 1998 JP 10168453 A2 19980623 Heisei. CAN 129:142670. (12) Mazal, C.; Paraskos, A. J.; Michl, J. J. Org. Chem. 1998, 63, 2116. (13) Stroeter, T.; Szeimies, G. J. Am. Chem. Soc. 1999, 121, 7476. (14) Bunz, U.; Szeimies, G. Tetrahedron Lett. 1990, 31, 651. (15) Schlueter, A. D.; Wegner, G.; Feast, W. J. Angew. Chem. 1988, 100, 283. (16) Belzner, J.; Szeimies, G. Tetrahedron Lett. 1987, 28, 3099. (17) Bothe, H.; Schlueter, A. D. AdV. Mater. 1991, 3, 440. (18) (a) Freudenberger, R.; Lamer, W.; Schlueter, A. D. J. Org. Chem. 1993, 58, 6497-6498. (b) Lassale, I.; Schmidt, M.; Schlueter, A. D. Acta Polymer 1994, 45, 389.
In this paper, we report the preparation of cis-endo 1,2,3,4tetrafunctionalized bicyclo[1.1.1]pentanes (Scheme 1, struc-
tricyclic ring system, making the overall yield of 5 from 2 less than ∼25%.
Scheme 1
Scheme 3
ture A); this type of structure has also been a target for others.20 The retrosynthetic approach to structure A (Scheme 1) uses tetracyclo[3.2.0.01,6.02,6]heptane (1)21 as a starting point since [1.1.1]propellanes are known to undergo addition across the transannular bond to yield doubly bridgehead substituted bicyclo[1.1.1]pentanes. Subsequent derivatization by hydrogen atom abstraction should occur preferentially at the ethano bridge, and not the quite unreactive, bicyclopentane cage. The tetracycloheptane 1 is accessible in 50% yield from tricyclo[3.1.0.02,6]hexane (2),22 obtained by the reduction of benzvalene.23,24 Inspired by the Szeimies25 procedure for the preparation of solvent-free [1.1.1]propellane, we have improved the isolation of 2 from the reaction mixture by converting it into the less volatile diiodo derivative 3 and subsequently regenerating 2 by reaction with potassium cyanide. The propellane bridgehead positions of 1 were functionalized by addition of biacetyl across the transannular bond followed by an oxidation of the resulting diketone 4 to the dicarboxylic acid 5 in a haloform reaction (Scheme 3), a
The low yield of the oxidation of 4 has prompted us to look for alternatives. Since the conversion of 2 into 1 is always accompanied by the formation of about 10-15% of the byproduct 6, we tried to maximize the yield of 6 and convert it to 5. A reaction with tert-butyllithium and carbon dioxide produced the monoacid 7. Since the hydrolysis of this chloromethyl derivative proved to be difficult, it was converted to an iodomethyl derivative by the Finkelstein reaction, hydrolyzed with sodium peroxide, and oxidized with potassium permanganate to yield 5 in an overall yield of 20% based on 2, which is, however, no better than the first procedure described above.
Scheme 4
Scheme 2
reaction sequence that gives excellent yields for the parent [1.1.1]propellane.26 However, the oxidation of 4 proceeds in ∼50% yield, perhaps due to a smaller stability of the (19) Freudenberger, R.; Claussen, W.; Schlueter, A.-D.; Wallmeier, H. Polymer 1994, 35, 4496. (20) Stulgies, B.; Pigg, D. P.; Kaszynski, P.; Kudzin, Z. H. Tetrahedron 2005, 61, 89. (21) Belzner, J.; Gareiss, B.; Polborn, K.; Schmid, W.; Semmler, K.; Szeimies, G. Chem. Ber. 1989, 122, 1509. (22) Christl, M.; Bruentrup, G. Chem. Ber. 1974, 107, 3908. (23) Katz, T. J.; Roth, R. J.; Acton, N.; Carnahan, E. J. J. Org. Chem. 1999, 64, 7663. (24) Katz, T. J.; Roth, R. J.; Acton, N.; Carnahan, E. J. Org. Synth. 1973, 53, 1824. (25) Alber, F.; Szeimies, G. Chem. Ber. 1992, 125, 757. (26) Levin, M. D.; Kaszynski, P.; Michl, J. Org. Synth. 2000, 77, 249. 750
As a crude guide to the regioselectivity of the halogenation of 5 to be expected in the next step, we estimated the s character of the carbon hybrid orbitals used to carry hydrogen atoms from 1JCH NMR coupling constants27 and obtained an encouraging result. For positions 2 and 5, the value was 31.3%, for 7, 29.3%, and for 3 and 4, 26.7% (Scheme 1, structure B). After many unsuccessful bromination attempts, we turned to chlorination, which succeeded. Chlorination of the dichloride of 5 in a mixture of liquid chlorine and carbon tetrachloride at -20 °C under irradiation with an incandescent lamp yielded mainly the 3-chloro derivative 8, and after extended reaction time, the 3,4-dichloro derivatives 9 and 10 (Scheme 5) in acceptable yields, plus rearranged and (27) The s character of carbon hybrid orbitals was calculated from 1JC-H coupling constants measured in dimethyl ester of 5 (1JC(2)-H ) 156.4 Hz, 1J 1 1 C(3)-H ) 133.3 Hz, JC(7)-H ) 146.7 Hz) using the equation JC-H ) 5 × %s (cf. Muller, N.; Pritchard, D. E. J. Chem. Phys. 1959, 31, 1471).
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Scheme 5
Scheme 6
overchlorinated products. At lower chlorine concentrations or at higher reaction temperatures, the formation of the desired products was too slow relative to a rearrangement of the tricyclic ring system, probably to structure 11 suggested by GC-MS.
tetraacid 16 was obtained by hydrolysis of the dicarboxamide diacid 14 or its monoester 13 with sodium peroxide31 and was characterized as its tetramethyl ester. An easy formation of the anhydride diacid 18 that was observed already during the isolation of 16 was completed upon heating above 80 °C for several hours. Following the retrosynthetic Scheme 1, hydrogen chloride elimination from the chloro derivatives was attempted. Surprisingly, none of the reagents tried succeeded with the monochloro derivative 8 or its various bridgehead protected derivatives, from alkaline hydroxide through sodium amide to Schlosser’s superbase.28 Fortunately, elimination with sodium amide in liquid ammonia succeeded with a mixture of dichloro derivatives 9 and 10 at room temperature and afforded the chloro olefin 12 in excellent yield. The vicinal isomer 9 reacted already at low temperature (-25 °C), but room temperature and longer reaction time (hours) were necessary for complete reaction of 10. The chloro olefin 12 is rather unstable and decomposes slowly in acetone, methanol, or chloroform solution, but solid samples can be stored in a refrigerator for weeks. Its ozonolysis in methanol at -60 °C gave the expected29 monomethyl ester 13 in good yield, and this was either hydrolyzed to the diacid 14 or methylated with diazomethane to the diester 15 (Scheme 6). Chemoselective transformations of either bridgehead or bridge-located functionalities (Scheme 6) provided access to several bicyclo[1.1.1]pentane-1,2,3,4-tetracarboxylic acid (16) derivatives with differentiated bridgehead and bridge substituents. Both carboxamide groups in the diester diamide 15 were hydrolyzed to carboxyls by sodium nitrite in a mixture of acetic acid and acetic anhydride,30 yielding the diester 17 with free carboxyls at the bridgeheads. The parent (28) Schlosser, M. Pure Appl. Chem. 1988, 60, 1627. (29) (a) Keul, H.; Griesbaum, K. Can. J. Chem. 1980, 58, 2049. (b) Griesbaum, K.; Keul, H. Angew. Chem. 1975, 87, 748. (30) Lin, R.; Castells, J.; Rapoport, H. J. Org. Chem. 1998, 63, 4069.
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Figure 1. An ORTEP representation of the diester 17.
The easy formation of 18 was not the only manifestation of an effect of close proximity of the bridge substituents on their reactivity. The diester 17 could not be reduced with LiAlH4, most probably for the same reason. This is reminiscent of a similar situation in 1,8- or 1,2-disubstituted naphthalenes,32,33 where crowded substituents not only (31) Vaughn, H. L.; Robbins, M. D. J. Org. Chem. 1975, 40, 1187. (32) Clayden, J.; Frampton, C. S.; McCarthy, C.; Westlund, N. Tetrahedron 1999, 55, 14161. (33) Clayden, J.; Westlund, N.; Frampton, C. S. J. Chem. Soc., Perkin Trans. 1 2000, 1379. 751
showed altered reactivity but also led to atropisomerism. According to the X-ray structure of 17 (Figure 1), the distance of the two bridge methoxycarbonyls (2.83 Å) is comparable with that in 1,8-disubstituted naphthalenes
(2.60-2.90 Å),34 and the ester groups prefer an antiparallel orientation, making the molecule chiral. Both enantiomers were found in the centrosymmetric crystals of 17 (space group P1h). The energy barrier to racemization in solution is probably low since no diastereomers of the chiral diamide 19 (Figure 2) were detected by low-temperature NMR measurements at -100 °C. In conclusion, we have developed a synthetic procedure for cis-endo-1,2,3,4-tetrasubstituted bicyclo[1.1.1]pentanes carrying different substituents in bridgehead and bridge positions. The proximity of the bridge substituents in the cis-endo configuration clearly affects their reactivity. It also opens an opportunity for a so far unobserved atropisomerism. Acknowledgment. We gratefully acknowledge financial support from the National Science Foundation, USA (Grant Nos. CHE-0446688 and OISE-0532040) and Ministry of Education, Youth and Sports, Czech Republic (Grant Nos. ME 571 and MSM0021622410). Supporting Information Available: Experimental procedures, full characterization for compounds, 1H and 13C NMR spectra, and CIF files for compounds 17 and 19. This material is available free of charge via the Internet at http://pubs.acs.org.
Figure 2. An ORTEP representation of the chiral diamide 19, which crystallizes with benzene.
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OL053039N (34) Clayden, J.; McCarthy, C.; Helliwell, M. Chem. Commun. 1999, 2059.
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